Genzyme Corporation

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Genzyme Corporation Drugs

Lemtrada

Lemtrada

2.1 Dosage Information

The recommended dosage of LEMTRADA is 12 mg/day administered by intravenous infusion for 2 treatment courses:
First Treatment Course: 12 mg/day on 5 consecutive days (60 mg total dose) Second Treatment Course: 12 mg/day on 3 consecutive days (36 mg total dose) administered 12 months after the first treatment course.
2.2 Vaccinations

Patients should complete any necessary immunizations at least 6 weeks prior to treatment with LEMTRADA [see Warnings and Precautions (5.9)].

Prior to LEMTRADA treatment determine whether patients have a history of varicella or have been vaccinated for varicella zoster virus (VZV). If not, test the patient for antibodies to VZV and consider vaccination for those who are antibody-negative. Postpone treatment with LEMTRADA until 6 weeks after VZV vaccination.

2.3 Recommended Premedication and Concomitant Medication

Corticosteroids

Premedicate patients with high dose corticosteroids (1,000 mg methylprednisolone or equivalent) immediately prior to LEMTRADA infusion and for the first 3 days of each treatment course [see Warnings and Precautions (5.2)].

Herpes Prophylaxis

Administer anti-viral prophylaxis for herpetic viral infections starting on the first day of each treatment course and continue for a minimum of two months following treatment with LEMTRADA or until the CD4+ lymphocyte count is ≥ 200 cells per microliter, whichever occurs later [see Warnings and Precautions (5.9)].

2.4 Preparation Instructions

Follow the steps below to prepare the diluted solution of LEMTRADA for intravenous infusion:
Inspect LEMTRADA visually for particulate matter and discoloration prior to administration. Do not use if particulate matter is present or the solution is discolored. Do not freeze or shake vials prior to use. Withdraw 1.2 mL of LEMTRADA from the vial into a syringe using aseptic technique and inject into a 100 mL bag of sterile 0.9% Sodium Chloride, USP or 5% Dextrose in Water, USP. Gently invert the bag to mix the solution. Ensure the sterility of the prepared solution, because it contains no antimicrobial preservatives. Each vial is for single use only.
Prior to administration, protect diluted LEMTRADA solution from light and store for as long as 8 hours either at room temperature 15°C to 25°C (59°F to 77°F) or keep refrigerated at conditions 2°C to 8°C (36°F to 46°F).

2.5 Infusion Instructions

Infuse LEMTRADA over 4 hours starting within 8 hours after dilution. Extend the duration of the infusion if clinically indicated.

Administer LEMTRADA in a setting in which equipment and personnel to appropriately manage anaphylaxis or serious infusion reactions are available [see Warnings and Precautions (5.4)].

Do not add or simultaneously infuse other drug substances through the same intravenous line. Do not administer as an intravenous push or bolus.

Monitor vital signs before the infusion and periodically during the infusion. Provide appropriate symptomatic treatment for infusion reactions as needed. Consider immediate discontinuation of the intravenous infusion if severe infusion reactions occur.

Observe patients for infusion reactions during and for at least 2 hours after each LEMTRADA infusion. Consider longer periods of observation if clinically indicated. Inform patients that they should report symptoms that occur during and after each infusion because they may indicate a need for prompt medical intervention [see Warnings and Precautions (5.2)].

2.6 Laboratory Testing and Monitoring to Assess Safety

Conduct the following laboratory tests at baseline and at periodic intervals for 48 months following the last treatment course of LEMTRADA in order to monitor for early signs of potentially serious adverse effects:
Complete blood count (CBC) with differential (prior to treatment initiation and at monthly intervals thereafter) Serum creatinine levels (prior to treatment initiation and at monthly intervals thereafter) Urinalysis with urine cell counts (prior to treatment initiation and at monthly intervals thereafter) A test of thyroid function, such as thyroid stimulating hormone (TSH) level (prior to treatment initiation and every 3 months thereafter)
Conduct baseline and yearly skin exams to monitor for melanoma [see Warnings and Precautions (5.3)].
Mozobil

Mozobil

2.1 Recommended Dosage and Administration

Vials should be inspected visually for particulate matter and discoloration prior to administration and should not be used if there is particulate matter or if the solution is discolored.

Begin treatment with Mozobil after the patient has received G-CSF once daily for four days. [see Dosage and Administration (2.2)] Administer Mozobil approximately 11 hours prior to initiation of each apheresis for up to 4 consecutive days.

The recommended dose of Mozobil is 0.24 mg/kg body weight by subcutaneous (SC) injection. Use the patient’s actual body weight to calculate the volume of Mozobil to be administered. Each vial delivers 1.2 mL of 20 mg/mL solution, and the volume to be administered to patients should be calculated from the following equation:

    0.012 X patient’s actual body weight (in kg) = volume to be administered (in mL)

In clinical studies, Mozobil dose has been calculated based on actual body weight in patients up to 175% of ideal body weight. Mozobil dose and treatment of patients weighing more than 175% of ideal body weight have not been investigated.

Based on increasing exposure with increasing body weight, the plerixafor dose should not exceed 40 mg/day. [see Clinical Pharmacology (12.3)]

2.2 Recommended Concomitant Medications

Administer daily morning doses of G-CSF 10 micrograms/kg for 4 days prior to the first evening dose of Mozobil and on each day prior to apheresis. [see Clinical Studies (14)]

2.3 Dosing in Renal Impairment

In patients with moderate and severe renal impairment (estimated creatinine clearance (CLCR) ≤ 50 mL/min), reduce the dose of Mozobil by one-third to 0.16 mg/kg as shown in Table 1. If CLCR is ≤ 50 mL/min the dose should not exceed 27 mg/day, as the mg/kg-based dosage results in increased plerixafor exposure with increasing body weight. [see Clinical Pharmacology (12.3)] Similar systemic exposure is predicted if the dose is reduced by one-third in patients with moderate and severe renal impairment compared with subjects with normal renal function. [see Clinical Pharmacology (12.3)]
Table 1: Recommended Dosage of Plerixafor in Patients with Renal Impairment      Estimated Creatinine Clearance     (mL/min) Dose > 50     0.24 mg/kg once daily (not to exceed 40 mg/day)      ≤ 50     0.16 mg/kg once daily (not to exceed 27 mg/day)
The following (Cockroft-Gault) formula may be used to estimate CLCR:

    Males:    Creatinine clearance (mL/min) = weight (kg) X (140 – age in years)                                                             72 X serum creatinine (mg/dL)

    Females:    Creatinine clearance (mL/min) = 0.85 X value calculated for males

There is insufficient information to make dosage recommendations in patients on hemodialysis.
Oxaliplatin

Oxaliplatin

The recommended dosage of Thymoglobulin for treatment of acute renal graft rejection is 1.5 mg/kg of body weight administered daily for 7 to 14 days. The recommended route of administration is intravenous infusion using a high-flow vein. Thymoglobulin should be infused over a minimum of 6 hours for the first infusion and over at least 4 hours on subsequent days of therapy.

Thymoglobulin should be administered through an in-line 0.22 micrometer filter.

Thymoglobulin is supplied as a 10 mL vial containing lyophilized (solid) Thymoglobulin (25 mg).

Please see Preparation for Administration for vial reconstitution and dilution in infusion solution recommendations. Investigations indicate that Thymoglobulin is less likely to produce side effects when administered at the recommended flow rate. Administration of antiviral prophylactic therapy is recommended. Premedication with corticosteroids, acetaminophen, and/or an antihistamine 1 hour prior to the infusion is recommended and may reduce the incidence and intensity of side effects during the infusion (See PRECAUTIONS: General and ADVERSE REACTIONS: Post-Marketing Experience). Medical personnel should monitor patients for adverse events during and after infusion. Monitoring T-cell counts (absolute and/or subsets) to assess the level of T-cell depletion is recommended. Total white blood cell and platelet counts should be monitored.

Overdosage of Thymoglobulin may result in leukopenia (including lymphopenia and neutropenia) and/or thrombocytopenia. The Thymoglobulin dose should be reduced by one-half if the WBC count is between 2,000 and 3,000 cells/mm3 or if the platelet count is between 50,000 and 75,000 cells/mm3. Stopping Thymoglobulin treatment should be considered if the WBC count falls below 2,000 cells/mm3 or platelets below 50,000 cells/mm3.

Preparation for Administration

Reconstitution

After calculating the number of vials needed, using aseptic technique, reconstitute each vial of Thymoglobulin with 5 mL of Sterile Water for Injection, USP (SWFI). Reconstituted Thymoglobulin is physically and chemically stable for up to 24 hours at room temperature; however, room temperature storage is not recommended. As Thymoglobulin contains no preservatives, reconstituted product should be used immediately.
Allow Thymoglobulin vials to reach room temperature before reconstituting the lyophilized product. Aseptically remove caps to expose rubber stoppers. Clean stoppers with germicidal or alcohol swab. Aseptically reconstitute each vial of Thymoglobulin lyophilized powder with the 5 mL of SWFI. Rotate vial gently until powder is completely dissolved. Each reconstituted vial contains 25 mg or 5 mg/mL of Thymoglobulin. Inspect solution for particulate matter after reconstitution. Should some particulate matter remain, continue to gently rotate the vial until no particulate matter is visible. If particulate matter persists, discard this vial.
Dilution
Transfer the contents of the calculated number of Thymoglobulin vials into the bag of infusion solution (saline or dextrose). Recommended volume: per one vial of Thymoglobulin use 50 mL of infusion solution (total volume usually between 50 to 500 mL). Mix the solution by inverting the bag gently only once or twice.
Infusion
Follow the manufacturer's instructions for the infusion administration set. Infuse through a 0.22 micrometer filter into a high-flow vein. Set the flow rate to deliver the dose over a minimum of 6 hours for the first dose and over at least 4 hours for subsequent doses.
Hectorol

Hectorol

Adult Administration:

The optimal dose of Hectorol must be carefully determined for each patient. Table 4 provides the current recommended therapeutic target levels for iPTH in patients with chronic kidney disease:
Table 4: Target Range of Intact Plasma PTH by Stage of CKD CKD Stage GFR(mL/min/1.73m2) Target “intact” PTH(pg/mL)
From Table 15 of National Kidney Foundation, K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 42:S1-S202, 2003 (suppl 3)
3 30-59 35-70 4 15-29 70-110 5 < 15 (or dialysis) 150-300
Dialysis:

The recommended initial dose of Hectorol is 10 mcg administered three times weekly at dialysis (approximately every other day). The initial dose should be adjusted, as needed, in order to lower blood iPTH into the range of 150 to 300 pg/mL. The dose may be increased at 8-week intervals by 2.5 mcg if iPTH is not lowered by 50% and fails to reach the target range. The maximum recommended dose of Hectorol is 20 mcg administered three times a week at dialysis for a total of 60 mcg per week. Drug administration should be suspended if iPTH falls below 100 pg/mL and restarted one week later at a dose that is at least 2.5 mcg lower than the last administered dose. During titration, iPTH, serum calcium, and serum phosphorus levels should be obtained weekly. If hypercalcemia, hyperphosphatemia, or a serum calcium times serum phosphorus product greater than 55 mg2/dL2 is noted, the dose of Hectorol should be decreased or suspended and/or the dose of phosphate binders should be appropriately adjusted. If suspended, the drug should be restarted at a dose that is at least 2.5 mcg lower.

Dosing must be individualized and based on iPTH levels with monitoring of serum calcium and serum phosphorus levels. The following is a suggested approach in dose titration:
Table 5: Dialysis Dosing Recommendations Initial Dosing
iPTH Level

Hectorol® Dose

> 400 pg/mL

10 mcg three times per week at dialysis
Dose Titration
iPTH Level

Hectorol® Dose

Above 300 pg/mL

Increase by 2.5 mcg at eight-week intervals as necessary

150 - 300 pg/mL

Maintain

< 100 pg/mL

Suspend for one week, then resume at a dose that is at least 2.5 mcg lower

Pre-dialysis:

The recommended initial dose of Hectorol is 1 mcg administered once daily. The initial dose should be adjusted, as needed, in order to lower blood iPTH to within target ranges (see table below). The dose may be increased at 2-week intervals by 0.5 mcg to achieve the target range of iPTH. The maximum recommended dose of Hectorol is 3.5 mcg administered once per day.

Serum levels of calcium and phosphorus and plasma levels of iPTH should be monitored at least every two weeks for 3 months after initiation of Hectorol therapy or following dose adjustments in Hectorol therapy, then monthly for 3 months, and every 3 months thereafter. If hypercalcemia, hyperphosphatemia, or a serum calcium times phosphorus product greater than 55 mg2/dL2 is noted, the dose of Hectorol should be decreased or suspended and/or the dose of phosphate binders should be appropriately adjusted. If suspended, the drug should be restarted at a dose that is at least 0.5 mcg lower.

Dosing must be individualized and based on iPTH levels with monitoring of serum calcium and serum phosphorus levels. Table 6 presents a suggested approach in dose titration:
Table 6: Pre-dialysis Dosing Recommendations Initial Dosing
iPTH Level

Hectorol® Dose

> 70 pg/mL (Stage 3)

1 mcg once per day

> 110 pg/mL (Stage 4)
Dose Titration
iPTH Level

Hectorol® Dose

Above 70 pg/mL (Stage 3)

Increase by 0.5 mcg at two-week intervals as necessary

110 pg/mL (Stage 4)

35 - 70 pg/mL (Stage 3)

Maintain

70 - 110 pg/mL (Stage 4)

< 35 pg/mL (Stage 3)

Suspend for one week, then resume at a dose that is at least 0.5 mcg lower

< 70 pg/mL (Stage 4)
Cerezyme

Cerezyme

Cerezyme® (imiglucerase for injection) is administered by intravenous infusion over 1-2 hours. Dosage should be individualized to each patient. Initial dosages range from 2.5 U/kg of body weight 3 times a week to 60 U/kg once every 2 weeks. 60 U/kg every 2 weeks is the dosage for which the most data are available. Disease severity may dictate that treatment be initiated at a relatively high dose or relatively frequent administration. Dosage adjustments should be made on an individual basis and may increase or decrease, based on achievement of therapeutic goals as assessed by routine comprehensive evaluations of the patient’s clinical manifestations.

Cerezyme® should be stored at 2-8°C (36-46°F). After reconstitution, Cerezyme should be inspected visually before use. Because this is a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after dilution. The diluted solution may be filtered through an in-line low protein-binding 0.2 μm filter during administration. Any vials exhibiting opaque particles or discoloration should not be used. DO NOT USE Cerezyme after the expiration date on the vial.

On the day of use, after the correct amount of Cerezyme to be administered to the patient has been determined, the appropriate number of vials are each reconstituted with Sterile Water for Injection, USP. The final concentrations and administration volumes are provided in the following table:
200 Unit Vial 400 Unit Vial Sterile water for reconstitution 5.1 mL 10.2 mL Final volume of reconstituted product 5.3 mL 10.6 mL Concentration after reconstitution 40 U/mL 40 U/mL Withdrawal volume 5.0 mL 10.0 mL Units of enzyme within final volume 200 units 400 units
A nominal 5.0 mL for the 200 unit vial (10.0 mL for the 400 unit vial) is withdrawn from each vial. The appropriate amount of Cerezyme for each patient is diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 – 200 mL. Cerezyme is administered by intravenous infusion over 1-2 hours. Aseptic techniques should be used when diluting the dose. Since Cerezyme does not contain any preservative, after reconstitution, vials should be promptly diluted and not stored for subsequent use. Cerezyme, after reconstitution, has been shown to be stable for up to 12 hours when stored at room temperature (25°C) and at 2-8°C. Cerezyme, when diluted, has been shown to be stable for up to 24 hours when stored at 2-8°C.

Relatively low toxicity, combined with the extended time course of response, allows small dosage adjustments to be made occasionally to avoid discarding partially used bottles. Thus, the dosage administered in individual infusions may be slightly increased or decreased to utilize fully each vial as long as the monthly administered dosage remains substantially unaltered.
Fabrazyme

Fabrazyme

2.1 Recommended Dose

The recommended dosage of Fabrazyme is 1 mg/kg body weight infused every two weeks as an intravenous (IV) infusion. Patients should receive antipyretics prior to infusion [see Warnings and Precautions (5.2)].

The initial IV infusion rate should be no more than 0.25 mg/min (15 mg/hr). The infusion rate may be slowed in the event of infusion reactions. After patient tolerance to the infusion is well established, the infusion rate may be increased in increments of 0.05 to 0.08 mg/min (increments of 3 to 5 mg/hr) with each subsequent infusion. For patients weighing < 30 kg, the maximum infusion rate should remain at 0.25 mg/min (15 mg/hr). For patients weighing ≥ 30 kg, the administration duration should not be less than 1.5 hours (based on individual patient tolerability).

Patients who have had a positive skin test to Fabrazyme or who have tested positive for anti-Fabrazyme IgE may be successfully re-challenged with Fabrazyme. The initial re-challenge administration should be a low dose at a lower infusion rate, e.g., 1/2 the therapeutic dose (0.5 mg/kg) at 1/25 the initial standard recommended rate (0.01 mg/min). Once a patient tolerates the infusion, the dose may be increased to reach the approved dose of 1 mg/kg and the infusion rate may be increased by slowly titrating upwards (doubled every 30 minutes up to a maximum rate of 0.25 mg/min), as tolerated.

2.2 Instructions for Use

Fabrazyme does not contain any preservatives. Vials are for single use only. Discard any unused product.

Avoid shaking or agitating this product. Do not use filter needles during the preparation of the infusion.

Reconstitution and Dilution (using Aseptic Technique)

Allow Fabrazyme vials and diluent to reach room temperature prior to reconstitution (approximately 30 minutes). The number of 35 mg and 5 mg vials needed is based on the patient’s body weight (kg) and the recommended dose of 1 mg/kg.

Select a combination of 35 mg and 5 mg vials so that the total number of mg is equal to or greater than the patient’s number of kg of body weight.

Reconstitute each 35 mg vial of Fabrazyme by slowly injecting 7.2 mL of Sterile Water for Injection, USP down the inside wall of each vial. Roll and tilt each vial gently. Each vial will yield a 5 mg/mL clear, colorless solution (total extractable amount per vial is 35 mg, 7 mL).

Reconstitute each 5 mg vial of Fabrazyme by slowly injecting 1.1 mL of Sterile Water for Injection, USP down the inside wall of each vial. Roll and tilt each vial gently. Each vial will yield a 5 mg/mL clear, colorless solution (total extractable amount per vial is 5 mg, 1 mL).

Visually inspect the reconstituted vials for particulate matter and discoloration. Do not use the reconstituted solution if there is particulate matter or if it is discolored.

The reconstituted solution should be further diluted with 0.9% Sodium Chloride Injection, USP to a total volume based on patient weight specified in Table 1 below. Prior to adding the volume of reconstituted Fabrazyme required for the patient dose, remove an equal volume of 0.9% Sodium Chloride Injection, USP from the infusion bag.
Table 1
   Patient Weight (kg)

  Minimum Total Volume (mL)

≤ 35

50

35.1 – 70

100

70.1 – 100

250

> 100

500

Patient dose (in mg) ÷ 5 mg/mL = Number of mL of reconstituted Fabrazyme required for patient dose

Example: Patient dose = 80 mg

80 mg ÷ 5 mg/mL = 16 mL of Fabrazyme

Slowly withdraw the reconstituted solution from each vial up to the total volume required for the patient dose. Inject the reconstituted Fabrazyme solution directly into the Sodium Chloride solution. Do not inject in the airspace within the infusion bag. Discard any vial with unused reconstituted solution.

Gently invert infusion bag to mix the solution, avoiding vigorous shaking and agitation.

Do not infuse Fabrazyme in the same intravenous line with other products.

Administer FABRAZYME using an in-line low protein binding 0.2 µm filter.

2.1 Recommended Dose

The recommended dosage of Fabrazyme is 1 mg/kg body weight infused every two weeks as an intravenous (IV) infusion. Patients should receive antipyretics prior to infusion [see Warnings and Precautions (5.2)].

The initial IV infusion rate should be no more than 0.25 mg/min (15 mg/hr). The infusion rate may be slowed in the event of infusion reactions. After patient tolerance to the infusion is well established, the infusion rate may be increased in increments of 0.05 to 0.08 mg/min (increments of 3 to 5 mg/hr) with each subsequent infusion. For patients weighing < 30 kg, the maximum infusion rate should remain at 0.25 mg/min (15 mg/hr). For patients weighing ≥ 30 kg, the administration duration should not be less than 1.5 hours (based on individual patient tolerability).

Patients who have had a positive skin test to Fabrazyme or who have tested positive for anti-Fabrazyme IgE may be successfully re-challenged with Fabrazyme. The initial re-challenge administration should be a low dose at a lower infusion rate, e.g., 1/2 the therapeutic dose (0.5 mg/kg) at 1/25 the initial standard recommended rate (0.01 mg/min). Once a patient tolerates the infusion, the dose may be increased to reach the approved dose of 1 mg/kg and the infusion rate may be increased by slowly titrating upwards (doubled every 30 minutes up to a maximum rate of 0.25 mg/min), as tolerated.

2.2 Instructions for Use

Fabrazyme does not contain any preservatives. Vials are for single use only. Discard any unused product.

Avoid shaking or agitating this product. Do not use filter needles during the preparation of the infusion.

Reconstitution and Dilution (using Aseptic Technique)

Allow Fabrazyme vials and diluent to reach room temperature prior to reconstitution (approximately 30 minutes). The number of 35 mg and 5 mg vials needed is based on the patient’s body weight (kg) and the recommended dose of 1 mg/kg.

Select a combination of 35 mg and 5 mg vials so that the total number of mg is equal to or greater than the patient’s number of kg of body weight.

Reconstitute each 35 mg vial of Fabrazyme by slowly injecting 7.2 mL of Sterile Water for Injection, USP down the inside wall of each vial. Roll and tilt each vial gently. Each vial will yield a 5 mg/mL clear, colorless solution (total extractable amount per vial is 35 mg, 7 mL).

Reconstitute each 5 mg vial of Fabrazyme by slowly injecting 1.1 mL of Sterile Water for Injection, USP down the inside wall of each vial. Roll and tilt each vial gently. Each vial will yield a 5 mg/mL clear, colorless solution (total extractable amount per vial is 5 mg, 1 mL).

Visually inspect the reconstituted vials for particulate matter and discoloration. Do not use the reconstituted solution if there is particulate matter or if it is discolored.

The reconstituted solution should be further diluted with 0.9% Sodium Chloride Injection, USP to a total volume based on patient weight specified in Table 1 below. Prior to adding the volume of reconstituted Fabrazyme required for the patient dose, remove an equal volume of 0.9% Sodium Chloride Injection, USP from the infusion bag.
Table 1
   Patient Weight (kg)

  Minimum Total Volume (mL)

≤ 35

50

35.1 – 70

100

70.1 – 100

250

> 100

500

Patient dose (in mg) ÷ 5 mg/mL = Number of mL of reconstituted Fabrazyme required for patient dose

Example: Patient dose = 80 mg

80 mg ÷ 5 mg/mL = 16 mL of Fabrazyme

Slowly withdraw the reconstituted solution from each vial up to the total volume required for the patient dose. Inject the reconstituted Fabrazyme solution directly into the Sodium Chloride solution. Do not inject in the airspace within the infusion bag. Discard any vial with unused reconstituted solution.

Gently invert infusion bag to mix the solution, avoiding vigorous shaking and agitation.

Do not infuse Fabrazyme in the same intravenous line with other products.

Administer FABRAZYME using an in-line low protein binding 0.2 µm filter.
Clolar

Clolar

2.1 Recommended Dosage

Administer the recommended pediatric dose of 52 mg/m2 as an intravenous infusion over 2 hours daily for 5 consecutive days.
Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2 to 6 weeks. The dosage is based on the patient's body surface area (BSA), calculated using the actual height and weight before the start of each cycle. To prevent drug incompatibilities, no other medications should be administered through the same intravenous line. Provide supportive care, such as intravenous fluids, antihyperuricemic treatment, and alkalinize urine throughout the 5 days of Clolar administration to reduce the effects of tumor lysis and other adverse events. Discontinue Clolar if hypotension develops during the 5 days of administration. Monitor renal and hepatic function during the 5 days of Clolar administration [see Warnings and Precautions (5.6, 5.7)]. Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of Clolar. Reduce the dose by 50% in patients with creatinine clearance (CrCL) between 30 and 60 mL/min. There is insufficient information to make a dosage recommendation in patients with CrCL less than 30 mL/min [see Use in Specific Populations (8.7)].
2.2 Supportive Medications and Medications to Avoid
Consider prophylactic anti-emetic medications as Clolar is moderately emetogenic. Consider the use of prophylactic steroids to mitigate Systemic Inflammatory Response Syndrome (SIRS) or capillary leak syndrome (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema). Minimize exposure to drugs with known renal toxicity during the 5 days of Clolar administration since the risk of renal toxicity may be increased. Consider avoiding concomitant use of medications known to induce hepatic toxicity.
2.3 Dose Modifications and Reinitiation of Therapy
Hematologic Toxicity Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patient's ANC is ≥ 0.75 × 109/L. If a patient experiences a Grade 4 neutropenia (ANC <0.5 × 109/L) lasting ≥4 weeks, reduce dose by 25% for the next cycle. Non-hematologic Toxicity Withhold Clolar if a patient develops a clinically significant infection, until the infection is controlled, then restart at the full dose. Withhold Clolar for a Grade 3 non-infectious non-hematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting controlled by antiemetic therapy). Re-institute Clolar administration at a 25% dose reduction when resolution or return to baseline. Discontinue Clolar administration for a Grade 4 non-infectious non-hematologic toxicity. Discontinue Clolar administration if a patient shows early signs or symptoms of SIRS or capillary leak (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures. Discontinue Clolar administration if Grade 3 or higher increases in creatinine or bilirubin are noted. Re-institute Clolar with a 25% dose reduction, when the patient is stable and organ function has returned to baseline. If hyperuricemia is anticipated (tumor lysis), initiate measures to control uric acid.
2.4 Reconstitution/Preparation

Clolar should be filtered through a sterile 0.2 micron syringe filter and then diluted with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous (IV) infusion to a final concentration between 0.15 mg/mL and 0.4 mg/mL. Use within 24 hours of preparation. Store diluted Clolar at room temperature (15–30ºC).

2.5 Incompatibilities

Do not administer any other medications through the same intravenous line.
Amlodipine Besylate

Amlodipine Besylate

Patients Not Taking a Phosphate Binder. The recommended starting dose of Renagel is 800 to 1600 mg, which can be administered as one or two 800 mg Renagel® Tablets or two to four 400 mg Renagel® Tablets, with meals based on serum phosphorus level. Table 1 provides recommended starting doses of Renagel for patients not taking a phosphate binder.
Table 1. Starting Dose for Dialysis Patients Not Taking a Phosphate Binder Serum Phosphorus Renagel® 800 mg Renagel® 400 mg
> 5.5 and < 7.5 mg/dL

1 tablet three times daily with meals

2 tablets three times daily with meals

≥ 7.5 and < 9.0 mg/dL

2 tablets three times daily with meals

3 tablets three times daily with meals

≥ 9.0 mg/dL

2 tablets three times daily with meals

4 tablets three times daily with meals

Patients Switching From Calcium Acetate. In a study in 84 CKD patients on hemodialysis, a similar reduction in serum phosphorus was seen with equivalent doses (approximately mg for mg) of Renagel and calcium acetate. Table 2 gives recommended starting doses of Renagel based on a patient's current calcium acetate dose.
Table 2. Starting Dose for Dialysis Patients Switching From Calcium Acetate to Renagel Calcium Acetate 667 mg(Tablets per meal) Renagel® 800 mg(Tablets per meal) Renagel® 400 mg (Tablets per meal)
1 tablet

1 tablet

2 tablets

2 tablets

2 tablets

3 tablets

3 tablets

3 tablets

5 tablets

Dose Titration for All Patients Taking Renagel. Dosage should be adjusted based on the serum phosphorus concentration with a goal of lowering serum phosphorus to 5.5 mg/dL or less. The dose may be increased or decreased by one tablet per meal at two week intervals as necessary. Table 3 gives a dose titration guideline. The average dose in a Phase 3 trial designed to lower serum phosphorus to 5.0 mg/dL or less was approximately three Renagel 800 mg tablets per meal. The maximum average daily Renagel dose studied was 13 grams.
Table 3. Dose Titration Guideline Serum Phosphorus Renagel® Dose
>5.5 mg/dL

Increase 1 tablet per meal at 2 week intervals

3.5 - 5.5 mg/dL

Maintain current dose

<3.5 mg/dL

Decrease 1 tablet per meal
Leukine

Leukine

Neutrophil Recovery Following Chemotherapy in Acute Myelogenous Leukemia

The recommended dose is 250 mcg/m2/day administered intravenously over a 4 hour period starting approximately on day 11 or four days following the completion of induction chemotherapy, if the day 10 bone marrow is hypoplastic with <5% blasts. If a second cycle of induction chemotherapy is necessary, LEUKINE should be administered approximately four days after the completion of chemotherapy if the bone marrow is hypoplastic with <5% blasts. LEUKINE should be continued until an ANC >1500 cells/mm3 for 3 consecutive days or a maximum of 42 days. LEUKINE should be discontinued immediately if leukemic regrowth occurs. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates.

In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3 or ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during LEUKINE therapy. LEUKINE treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm3.

Mobilization of Peripheral Blood Progenitor Cells

The recommended dose is 250 mcg/m2/day administered IV over 24 hours or SC once daily. Dosing should continue at the same dose through the period of PBPC collection. The optimal schedule for PBPC collection has not been established. In clinical studies, collection of PBPC was usually begun by day 5 and performed daily until protocol specified targets were achieved (see CLINICAL EXPERIENCE, Mobilization and Engraftment of PBPC). If WBC > 50,000 cells/mm3, the LEUKINE dose should be reduced by 50%. If adequate numbers of progenitor cells are not collected, other mobilization therapy should be considered.

Post Peripheral Blood Progenitor Cell Transplantation

The recommended dose is 250 mcg/m2/day administered IV over 24 hours or SC once daily beginning immediately following infusion of progenitor cells and continuing until an ANC>1500 cells/mm3 for three consecutive days is attained.

Myeloid Reconstitution After Autologous or Allogeneic Bone Marrow Transplantation

The recommended dose is 250 mcg/m2/day administered IV over a 2-hour period beginning two to four hours after bone marrow infusion, and not less than 24 hours after the last dose of chemotherapy or radiotherapy. Patients should not receive LEUKINE until the post marrow infusion ANC is less than 500 cells/mm3. LEUKINE should be continued until an ANC >1500 cells/mm3 for three consecutive days is attained. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. LEUKINE should be discontinued immediately if blast cells appear or disease progression occurs.

In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3, ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during LEUKINE therapy. LEUKINE treatment should be interrupted or the dose reduced by 50% if the ANC exceeds 20,000 cells/mm3.

Bone Marrow Transplantation Failure or Engraftment Delay

The recommended dose is 250 mcg/m2/day for 14 days as a 2-hour IV infusion. The dose can be repeated after 7 days off therapy if engraftment has not occurred. If engraftment still has not occurred, a third course of 500 mcg/m2/day for 14 days may be tried after another 7 days off therapy. If there is still no improvement, it is unlikely that further dose escalation will be beneficial. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. LEUKINE should be discontinued immediately if blast cells appear or disease progression occurs.

In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3, ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during LEUKINE therapy. LEUKINE treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm3.

Preparation of LEUKINE
Liquid LEUKINE is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial. Lyophilized LEUKINE is a sterile, white, preservative-free powder (250 mcg) that requires reconstitution with 1 mL Sterile Water for Injection, USP, or 1 mL Bacteriostatic Water for Injection, USP. Liquid LEUKINE may be stored for up to 20 days at 2-8°C once the vial has been entered. Discard any remaining solution after 20 days. Lyophilized LEUKINE (250 mcg) should be reconstituted aseptically with 1.0 mL of diluent (see below). The contents of vials reconstituted with different diluents should not be mixed together. Sterile Water for Injection, USP (without preservative): Lyophilized LEUKINE vials contain no antibacterial preservative, and therefore solutions prepared with Sterile Water for Injection, USP should be administered as soon as possible, and within 6 hours following reconstitution and/or dilution for IV infusion. The vial should not be re-entered or reused. Do not save any unused portion for administration more than 6 hours following reconstitution. Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol): Reconstituted solutions prepared with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) may be stored for up to 20 days at 2-8°C prior to use. Discard reconstituted solution after 20 days. Previously reconstituted solutions mixed with freshly reconstituted solutions must be administered within 6 hours following mixing. Preparations containing benzyl alcohol (including liquid LEUKINE and lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection) should not be used in neonates (see WARNINGS). During reconstitution of lyophilized LEUKINE the diluent should be directed at the side of the vial and the contents gently swirled to avoid foaming during dissolution. Avoid excessive or vigorous agitation; do not shake. LEUKINE should be used for SC injection without further dilution. Dilution for IV infusion should be performed in 0.9% Sodium Chloride Injection, USP. If the final concentration of LEUKINE is below 10 mcg/mL, Albumin (Human) at a final concentration of 0.1% should be added to the saline prior to addition of LEUKINE to prevent adsorption to the components of the drug delivery system. To obtain a final concentration of 0.1% Albumin (Human), add 1 mg Albumin (Human) per 1 mL 0.9% Sodium Chloride Injection, USP (e.g., use 1 mL 5% Albumin [Human] in 50 mL 0.9% Sodium Chloride Injection, USP). An in-line membrane filter should NOT be used for intravenous infusion of LEUKINE. Store liquid LEUKINE and reconstituted lyophilized LEUKINE solutions under refrigeration at 2–8°C (36–46°F); DO NOT FREEZE. In the absence of compatibility and stability information, no other medication should be added to infusion solutions containing LEUKINE. Use only 0.9% Sodium Chloride Injection, USP to prepare IV infusion solutions. Aseptic technique should be employed in the preparation of all LEUKINE solutions. To assure correct concentration following reconstitution, care should be exercised to eliminate any air bubbles from the needle hub of the syringe used to prepare the diluent. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present or the solution is discolored, the vial should not be used.
Hectorol

Hectorol

Adult Administration:

For intravenous use only. The optimal dose of Hectorol must be carefully determined for each patient.

The recommended initial dose of Hectorol is 4 mcg administered intravenously as a bolus dose three times weekly at the end of dialysis (approximately every other day). The initial dose should be adjusted, as needed, in order to lower blood iPTH into the range of 150 to 300 pg/mL. The dose may be increased at 8-week intervals by 1 to 2 mcg if iPTH is not lowered by 50% and fails to reach the target range. Dosages higher than 18 mcg weekly have not been studied. Drug administration should be suspended if iPTH falls below 100 pg/mL and restarted one week later at a dose that is at least 1 mcg lower than the last administered dose. During titration, iPTH, serum calcium, and serum phosphorus levels should be obtained weekly. If hypercalcemia, hyperphosphatemia, or a serum calcium times phosphorus product greater than 55 mg2/dL2 is noted, the dose of Hectorol should be decreased or suspended and/or the dose of phosphate binders should be appropriately adjusted. If suspended, the drug should be restarted at a dose that is 1 mcg lower.

Dosing must be individualized and based on iPTH levels with monitoring of serum calcium and serum phosphorus levels. Table 5 presents a suggested approach in dose titration.
Table 5: Initial Dosing iPTH Level Hectorol® Dose >400 pg/mL 4 mcg three times per week at the end of dialysis, or approximately every other day Dose Titration iPTH Level Hectorol® Dose Decrease by <50% and above 300 pg/mL Increase by 1 to 2 mcg at eight-week intervals as necessary Decrease by >50% and above 300 pg/mL Maintain 150 - 300 pg/mL Maintain <100 pg/mL Suspend for one week, then resume at a dose that is at least 1 mcg lower

Multi-Dose Vial

After initial vial use, the contents of the multi-dose vial remain stable up to 3 days when stored at 2–8°C (36-46°F). Discard unused portion of multi-dose vial after 3 days. (see HOW SUPPLIED and STORAGE section).
Carticel

Carticel

For Autologous Implantation Only
2.1 Dosage

Patients in the Swedish series [see Clinical Studies (14)] received a wide range of cell doses per cm2 of defect. Available data on 70 of 78 patients with femoral condyle defects showed a median dose of 1.6 million cells/cm2 of defect. The middle 80% of these patients received from 0.64 million to 3.3 million cells/cm2.

Each Carticel finished product vial contains approximately 12 million cells. Genzyme provides a single vial for each defect measuring ≤ 7 cm2. Two vials of Carticel are provided for defects 7 to 14 cm2, and three vials are provided for defects > 14cm2. This is based on Genzyme’s greater than 10 years of experience with Carticel.

2.2 Handling Precautions and Preparation

2.2.1 Handling Precautions

The Carticel product is intended solely for autologous use. Prior to Carticel implantation, match the patient name and ID number on the certificate of analysis to the patient’s chart and the patient ID on the shipping box, transport cylinder and vial.

Healthcare providers should employ universal precautions in handling the biopsy samples and the Carticel product [[see Risk of Transmissible Infectious Diseases (5.2)].

Refer to the Indications and Usage (1) and Warnings and Precautions (5) Sections for additional considerations regarding the use of Carticel.

2.2.2 Preparation

NOTE:

The exterior of the Carticel vial containing the cultured cells is NOT sterile. Follow strict sterile technique protocols.

When treating a defect that requires multiple vials of cells, resuspend, aspirate and inject one vial at a time.
Remove red plastic lid from vial. Wipe the vial surface and lid with alcohol. Inspect vial contents for particulates, discoloration or turbidity. The cellular product appears as a yellowish clump in the bottom of the vial. Do not administer if contents appear turbid prior to cell suspension. While holding vial in a vertical position, insert the needle of the intraspinal catheter into the vial. The needle must be positioned just above the fluid level. Slowly remove the inner needle from the catheter, leaving flexible tip behind. Attach a tuberculin syringe to catheter. Lower the catheter tip into the media and position just above the cell pellet. Aspirate all the medium from the vial leaving only the cell pellet behind. Slowly expel medium back into the vial. This action will break the cell pellet and resuspend the cells in the medium. Lower the catheter tip to the base of the vial and aspirate all contents into syringe, leaving the vial empty. Slowly inject the contents into the vial again. This will assure complete suspension of the cells. Repeat these steps as needed to ensure all cells are resuspended. Cell resuspension is complete when cell particles are no longer apparent, and the medium is a consistent, “cloudy” mixture. Aspirate all contents of vial into syringe. Always hold syringe vertical to keep an air pocket at the proximal end of syringe.
2.3 Administration

Implantation of the Carticelproduct should be restricted to physicians who have completed Genzyme Biosurgery’s Surgeon Training Program.

Implantation of the Carticel product is performed during arthrotomy and requires both preparation of the defect bed and a periosteal flap to secure the implant. Complete hemostasis must be achieved prior to periosteal fixation and cell implantation. See the Carticel Surgical Manual, Genzyme document #65021 for instructions on the performance of these procedures.

2.3.1 Implantation
Insert the catheter tip through the superior opening of the periosteal chamber at the site of the defect. Advance catheter to most inferior aspect of the defect. Slowly inject a cell dose while moving the catheter tip from side to side and withdrawing the catheter proximally. This will ensure an even distribution of the cells throughout the defect. Complete the implantation by closing the superior opening of the periosteum as instructed. See Carticel Surgical Manual, Genzyme document #65021.
Thyrogen

Thyrogen

2.1 Recommended Dosage

THYROGEN should be used by physicians knowledgeable in the management of patients with thyroid cancer.

THYROGEN is indicated as a two-injection regimen. The recommended dosage of THYROGEN is a 0.9 mg intramuscular injection to the buttock followed by a second 0.9 mg intramuscular injection to the buttock 24 hours later.

THYROGEN should be administered intramuscularly only. THYROGEN should not be administered intravenously.

Pretreatment with glucocorticoids should be considered for patients in whom tumor expansion may compromise vital anatomic structures [see Warnings and Precautions (5.3)].

Routine measurement of serum TSH levels is not recommended after THYROGEN use.

2.2 Reconstitution, Preparation, and Administration of THYROGEN

The supplied lyophilized powder must be reconstituted with Sterile Water for Injection. THYROGEN should be prepared, and administered in the following manner:
Add 1.2 mL of Sterile Water for Injection to the vial containing the THYROGEN lyophilized powder. Swirl the contents of the vial until all the material is dissolved. Do not shake the solution. The reconstituted THYROGEN solution has a concentration of 0.9 mg of thyrotropin alfa per mL. Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration. The reconstituted THYROGEN solution should be clear and colorless. Do not use if the solution has particulate matter or is cloudy or discolored. Withdraw 1 mL of the reconstituted THYROGEN solution (0.9 mg of thyrotropin alfa) and inject intramuscularly in the buttocks. The reconstituted THYROGEN solution must be injected within 3 hours unless refrigerated; if refrigerated, the reconstituted solution may be kept for up to 24 hours. Discard unused portions. Do not mix with other substances.
2.3 Timing of Serum Thyroglobulin Testing Following THYROGEN Administration

For serum thyroglobulin testing, the serum sample should be obtained 72 hours after the final injection of THYROGEN [see Clinical Studies (14.1)].

2.4 Timing for Remnant Ablation and Diagnostic Scanning Following THYROGEN Administration

Oral radioiodine should be given 24 hours after the second injection of THYROGEN in both remnant ablation and diagnostic scanning. The activity of 131I is carefully selected at the discretion of the nuclear medicine physician.

Diagnostic scanning should be performed 48 hours after the radioiodine administration.

2.1 Recommended Dosage

THYROGEN should be used by physicians knowledgeable in the management of patients with thyroid cancer.

THYROGEN is indicated as a two-injection regimen. The recommended dosage of THYROGEN is a 0.9 mg intramuscular injection to the buttock followed by a second 0.9 mg intramuscular injection to the buttock 24 hours later.

THYROGEN should be administered intramuscularly only. THYROGEN should not be administered intravenously.

Pretreatment with glucocorticoids should be considered for patients in whom tumor expansion may compromise vital anatomic structures [see Warnings and Precautions (5.3)].

Routine measurement of serum TSH levels is not recommended after THYROGEN use.

2.2 Reconstitution, Preparation, and Administration of THYROGEN

The supplied lyophilized powder must be reconstituted with Sterile Water for Injection. THYROGEN should be prepared, and administered in the following manner:
Add 1.2 mL of Sterile Water for Injection to the vial containing the THYROGEN lyophilized powder. Swirl the contents of the vial until all the material is dissolved. Do not shake the solution. The reconstituted THYROGEN solution has a concentration of 0.9 mg of thyrotropin alfa per mL. Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration. The reconstituted THYROGEN solution should be clear and colorless. Do not use if the solution has particulate matter or is cloudy or discolored. Withdraw 1 mL of the reconstituted THYROGEN solution (0.9 mg of thyrotropin alfa) and inject intramuscularly in the buttocks. The reconstituted THYROGEN solution must be injected within 3 hours unless refrigerated; if refrigerated, the reconstituted solution may be kept for up to 24 hours. Discard unused portions. Do not mix with other substances.
2.3 Timing of Serum Thyroglobulin Testing Following THYROGEN Administration

For serum thyroglobulin testing, the serum sample should be obtained 72 hours after the final injection of THYROGEN [see Clinical Studies (14.1)].

2.4 Timing for Remnant Ablation and Diagnostic Scanning Following THYROGEN Administration

Oral radioiodine should be given 24 hours after the second injection of THYROGEN in both remnant ablation and diagnostic scanning. The activity of 131I is carefully selected at the discretion of the nuclear medicine physician.

Diagnostic scanning should be performed 48 hours after the radioiodine administration.
Myozyme

Myozyme

2.1 Recommended Dose

The recommended dosage regimen of MYOZYME is 20 mg/kg body weight administered every 2 weeks as an intravenous infusion.

2.2 Instructions for Use

MYOZYME does not contain any preservatives. Vials are single-use only. Any unused product should be discarded.

The total volume of infusion is determined by the patient’s body weight and should be administered over approximately 4 hours.

Infusions should be administered in a step-wise manner using an infusion pump. The initial infusion rate should be no more than 1 mg/kg/hr. The infusion rate may be increased by 2 mg/kg/hr every 30 minutes, after patient tolerance to the infusion rate is established, until a maximum rate of 7 mg/kg/hr is reached. Vital signs should be obtained at the end of each step. If the patient is stable, MYOZYME may be administered at the maximum rate of 7 mg/kg/hr until the infusion is completed. The infusion rate may be slowed and/or temporarily stopped in the event of infusion reactions. See Table 1 below for the rate of infusion at each step, expressed as mL/hr based on the recommended infusion volume by patient weight.
Table 1: Recommended Infusion Volumes and Rates Patient Weight Range (kg) Total infusion volume (mL)
Step 1

1 mg/kg/hr
(mL/hr)
Step 2

3 mg/kg/hr
(mL/hr)
Step 3

5 mg/kg/hr
(mL/hr)
Step 4

7 mg/kg/hr
(mL/hr) 1.25 - 10 50 3 8 13 18 10.1 - 20 100 5 15 25 35 20.1 - 30 150 8 23 38 53 30.1 - 35 200 10 30 50 70 35.1 - 50 250 13 38 63 88 50.1 - 60 300 15 45 75 105 60.1 - 100 500 25 75 125 175 100.1 - 120 600 30 90 150 210 120.1 - 140 700 35 105 175 245 140.1 - 160 800 40 120 200 280 160.1 - 180 900 45 135 225 315 180.1 - 200 1000 50 150 250 350
Reconstitution, dilution and administration

MYOZYME should be reconstituted, diluted and administered by a healthcare professional.

Use aseptic technique during preparation. Do not use filter needles during preparation.
Determine the number of vials to be reconstituted based on the individual patient’s weight and the recommended dose of 20 mg/kg.   Patient weight (kg) x dose (mg/kg) = patient dose (in mg)Patient dose (in mg) divided by 50 mg/vial = number of vials to reconstitute. If the number of vials includes a fraction, round up to the next whole number.Example: Patient weight (16 kg) x dose (20 mg/kg) = patient dose (320 mg)320 mg divided by 50 mg/vial = 6.4 vials; therefore, 7 vials should be reconstitutedRemove the required number of vials from the refrigerator and allow them to reach room temperature prior to reconstitution (approximately 30 minutes).

Reconstitute each MYOZYME vial by slowly injecting 10.3 mL of Sterile Water for Injection, USP to the inside wall of each vial. Each vial will yield 5 mg/mL. The total extractable dose per vial is 50 mg per 10 mL. Avoid forceful impact of the water for injection on the powder and avoid foaming. This is done by slow drop-wise addition of the water for injection down the inside of the vial and not directly onto the lyophilized cake. Tilt and roll each vial gently. Do not invert, swirl, or shake.

The reconstituted MYOZYME solution should be protected from light.

Perform an immediate visual inspection on the reconstituted vials for particulate matter and discoloration. If upon immediate inspection opaque particles are observed or if the solution is discolored do not use. The reconstituted solution may occasionally contain some alglucosidase alfa particles (typically less than 10 in a vial) in the form of thin white strands or translucent fibers subsequent to the initial inspection. This may also happen following dilution for infusion. These particles have been shown to contain alglucosidase alfa and may appear after the initial reconstitution step and increase over time. Studies have shown that these particles are removed via in-line filtration without having a detectable effect on the purity or strength.

MYOZYME should be diluted in 0.9% Sodium Chloride for Injection, USP, immediately after reconstitution, to a final MYOZYME concentration of 0.5 to 4 mg/mL. See Table 1 for the recommended total infusion volume based on patient weight.

Slowly withdraw the reconstituted solution from each vial. Avoid foaming in the syringe.

Remove airspace from the infusion bag to minimize particle formation due to the sensitivity of MYOZYME to air-liquid interfaces.

Add the reconstituted MYOZYME solution slowly and directly into the sodium chloride solution. Do not add directly into airspace that may remain within the infusion bag. Avoid foaming in the infusion bag.

Gently invert or massage the infusion bag to mix. Do not shake.

Administer MYOZYME using an in-line low protein-binding 0.2 µm filter.
MYOZYME should not be infused in the same intravenous line with other products.

MYOZYME does not contain any preservatives. Vials are single-use only. Discard any unused product.

2.1 Recommended Dose

The recommended dosage regimen of MYOZYME is 20 mg/kg body weight administered every 2 weeks as an intravenous infusion.

2.2 Instructions for Use

MYOZYME does not contain any preservatives. Vials are single-use only. Any unused product should be discarded.

The total volume of infusion is determined by the patient’s body weight and should be administered over approximately 4 hours.

Infusions should be administered in a step-wise manner using an infusion pump. The initial infusion rate should be no more than 1 mg/kg/hr. The infusion rate may be increased by 2 mg/kg/hr every 30 minutes, after patient tolerance to the infusion rate is established, until a maximum rate of 7 mg/kg/hr is reached. Vital signs should be obtained at the end of each step. If the patient is stable, MYOZYME may be administered at the maximum rate of 7 mg/kg/hr until the infusion is completed. The infusion rate may be slowed and/or temporarily stopped in the event of infusion reactions. See Table 1 below for the rate of infusion at each step, expressed as mL/hr based on the recommended infusion volume by patient weight.
Table 1: Recommended Infusion Volumes and Rates Patient Weight Range (kg) Total infusion volume (mL)
Step 1

1 mg/kg/hr
(mL/hr)
Step 2

3 mg/kg/hr
(mL/hr)
Step 3

5 mg/kg/hr
(mL/hr)
Step 4

7 mg/kg/hr
(mL/hr) 1.25 - 10 50 3 8 13 18 10.1 - 20 100 5 15 25 35 20.1 - 30 150 8 23 38 53 30.1 - 35 200 10 30 50 70 35.1 - 50 250 13 38 63 88 50.1 - 60 300 15 45 75 105 60.1 - 100 500 25 75 125 175 100.1 - 120 600 30 90 150 210 120.1 - 140 700 35 105 175 245 140.1 - 160 800 40 120 200 280 160.1 - 180 900 45 135 225 315 180.1 - 200 1000 50 150 250 350
Reconstitution, dilution and administration

MYOZYME should be reconstituted, diluted and administered by a healthcare professional.

Use aseptic technique during preparation. Do not use filter needles during preparation.
Determine the number of vials to be reconstituted based on the individual patient’s weight and the recommended dose of 20 mg/kg.   Patient weight (kg) x dose (mg/kg) = patient dose (in mg)Patient dose (in mg) divided by 50 mg/vial = number of vials to reconstitute. If the number of vials includes a fraction, round up to the next whole number.Example: Patient weight (16 kg) x dose (20 mg/kg) = patient dose (320 mg)320 mg divided by 50 mg/vial = 6.4 vials; therefore, 7 vials should be reconstitutedRemove the required number of vials from the refrigerator and allow them to reach room temperature prior to reconstitution (approximately 30 minutes).

Reconstitute each MYOZYME vial by slowly injecting 10.3 mL of Sterile Water for Injection, USP to the inside wall of each vial. Each vial will yield 5 mg/mL. The total extractable dose per vial is 50 mg per 10 mL. Avoid forceful impact of the water for injection on the powder and avoid foaming. This is done by slow drop-wise addition of the water for injection down the inside of the vial and not directly onto the lyophilized cake. Tilt and roll each vial gently. Do not invert, swirl, or shake.

The reconstituted MYOZYME solution should be protected from light.

Perform an immediate visual inspection on the reconstituted vials for particulate matter and discoloration. If upon immediate inspection opaque particles are observed or if the solution is discolored do not use. The reconstituted solution may occasionally contain some alglucosidase alfa particles (typically less than 10 in a vial) in the form of thin white strands or translucent fibers subsequent to the initial inspection. This may also happen following dilution for infusion. These particles have been shown to contain alglucosidase alfa and may appear after the initial reconstitution step and increase over time. Studies have shown that these particles are removed via in-line filtration without having a detectable effect on the purity or strength.

MYOZYME should be diluted in 0.9% Sodium Chloride for Injection, USP, immediately after reconstitution, to a final MYOZYME concentration of 0.5 to 4 mg/mL. See Table 1 for the recommended total infusion volume based on patient weight.

Slowly withdraw the reconstituted solution from each vial. Avoid foaming in the syringe.

Remove airspace from the infusion bag to minimize particle formation due to the sensitivity of MYOZYME to air-liquid interfaces.

Add the reconstituted MYOZYME solution slowly and directly into the sodium chloride solution. Do not add directly into airspace that may remain within the infusion bag. Avoid foaming in the infusion bag.

Gently invert or massage the infusion bag to mix. Do not shake.

Administer MYOZYME using an in-line low protein-binding 0.2 µm filter.
MYOZYME should not be infused in the same intravenous line with other products.

MYOZYME does not contain any preservatives. Vials are single-use only. Discard any unused product.

Reconstitution, dilution and administration

MYOZYME should be reconstituted, diluted and administered by a healthcare professional.

Use aseptic technique during preparation. Do not use filter needles during preparation.
Determine the number of vials to be reconstituted based on the individual patient’s weight and the recommended dose of 20 mg/kg.   Patient weight (kg) x dose (mg/kg) = patient dose (in mg)Patient dose (in mg) divided by 50 mg/vial = number of vials to reconstitute. If the number of vials includes a fraction, round up to the next whole number.Example: Patient weight (16 kg) x dose (20 mg/kg) = patient dose (320 mg)320 mg divided by 50 mg/vial = 6.4 vials; therefore, 7 vials should be reconstitutedRemove the required number of vials from the refrigerator and allow them to reach room temperature prior to reconstitution (approximately 30 minutes).

Reconstitute each MYOZYME vial by slowly injecting 10.3 mL of Sterile Water for Injection, USP to the inside wall of each vial. Each vial will yield 5 mg/mL. The total extractable dose per vial is 50 mg per 10 mL. Avoid forceful impact of the water for injection on the powder and avoid foaming. This is done by slow drop-wise addition of the water for injection down the inside of the vial and not directly onto the lyophilized cake. Tilt and roll each vial gently. Do not invert, swirl, or shake.

The reconstituted MYOZYME solution should be protected from light.

Perform an immediate visual inspection on the reconstituted vials for particulate matter and discoloration. If upon immediate inspection opaque particles are observed or if the solution is discolored do not use. The reconstituted solution may occasionally contain some alglucosidase alfa particles (typically less than 10 in a vial) in the form of thin white strands or translucent fibers subsequent to the initial inspection. This may also happen following dilution for infusion. These particles have been shown to contain alglucosidase alfa and may appear after the initial reconstitution step and increase over time. Studies have shown that these particles are removed via in-line filtration without having a detectable effect on the purity or strength.

MYOZYME should be diluted in 0.9% Sodium Chloride for Injection, USP, immediately after reconstitution, to a final MYOZYME concentration of 0.5 to 4 mg/mL. See Table 1 for the recommended total infusion volume based on patient weight.

Slowly withdraw the reconstituted solution from each vial. Avoid foaming in the syringe.

Remove airspace from the infusion bag to minimize particle formation due to the sensitivity of MYOZYME to air-liquid interfaces.

Add the reconstituted MYOZYME solution slowly and directly into the sodium chloride solution. Do not add directly into airspace that may remain within the infusion bag. Avoid foaming in the infusion bag.

Gently invert or massage the infusion bag to mix. Do not shake.

Administer MYOZYME using an in-line low protein-binding 0.2 µm filter.
MYOZYME should not be infused in the same intravenous line with other products.

MYOZYME does not contain any preservatives. Vials are single-use only. Discard any unused product.
Atenolol

Atenolol

2.1 General Dosing Information

Before beginning treatment with KYNAMRO, measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin [see Warnings and Precautions (5.1)].

The recommended dose of KYNAMRO is 200 milligrams (mg) once weekly as a subcutaneous injection.

KYNAMRO is intended for subcutaneous use only. Do not administer intramuscularly or intravenously.

The injection should be given on the same day every week, but if a dose is missed, the injection should be given at least 3 days from the next weekly dose.

After initiation of KYNAMRO therapy lipid levels should be monitored at least every 3 months for the first year. Maximal reduction of LDL-C may be seen with KYNAMRO therapy after approximately 6 months (based on the time to steady state seen in clinical studies). Health care providers should assess the patient’s LDL-C level after 6 months to determine if the LDL-C reduction achieved with KYNAMRO is sufficiently robust to warrant the potential risk of liver toxicity.

2.2 Administration

Each pre-filled syringe of KYNAMRO provides 200 mg of mipomersen sodium in a deliverable volume of 1 milliliter (mL) of solution and is intended for single-use only.

The KYNAMRO pre-filled syringe should be removed from 2-8°C (36-46°F) refrigerated storage and allowed to reach room temperature for at least 30 minutes prior to administration.

Parenteral drug products should be inspected visually prior to administration. If the solution is cloudy or contains visible particulate matter, the contents must not be injected and the product should be returned to the pharmacy.

The first injection administered by the patient or caregiver should be performed under the guidance and supervision of an appropriately qualified health care professional.

KYNAMRO should be injected into the abdomen, thigh region, or outer area of the upper arm. KYNAMRO should not be injected in areas of active skin disease or injury such as sunburns, skin rashes, inflammation, skin infections, active areas of psoriasis, etc. Areas of tattooed skin and scarring should also be avoided.

2.3 Adjustments for Patients Developing Transaminase Elevations

Table 1 summarizes recommendations for monitoring for patients who develop elevated transaminases during therapy with KYNAMRO [see Warnings and Precautions (5.1)].
Table 1: Monitoring for Patients With Elevated Transaminases * Recommendations based on an ULN of approximately 30-40 international units/L. ALT or AST Treatment and monitoring recommendations* ≥ 3x and < 5x ULN Confirm elevation with a repeat measurement within one week. If confirmed, withhold dosing, obtain additional liver-related tests if not already measured (such as total bilirubin, alkaline phosphatase and INR) and investigate to identify the probable cause. If resuming KYNAMRO after transaminases resolve to <3x ULN consider monitoring liver-related tests more frequently. ≥ 5x ULN Withhold dosing, obtain additional liver-related tests if not already measured (such as total bilirubin, alkaline phosphatase and INR) and investigate to identify the probable cause. If resuming KYNAMRO after transaminases resolve to <3x ULN, monitor liver-related tests more frequently.
If transaminase elevations are accompanied by clinical symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥ 2x ULN, or active liver disease, discontinue treatment with KYNAMRO and investigate to identify the probable cause [see Warnings and Precautions (5.1)].

2.1 General Dosing Information

Before beginning treatment with KYNAMRO, measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin [see Warnings and Precautions (5.1)].

The recommended dose of KYNAMRO is 200 milligrams (mg) once weekly as a subcutaneous injection.

KYNAMRO is intended for subcutaneous use only. Do not administer intramuscularly or intravenously.

The injection should be given on the same day every week, but if a dose is missed, the injection should be given at least 3 days from the next weekly dose.

After initiation of KYNAMRO therapy lipid levels should be monitored at least every 3 months for the first year. Maximal reduction of LDL-C may be seen with KYNAMRO therapy after approximately 6 months (based on the time to steady state seen in clinical studies). Health care providers should assess the patient’s LDL-C level after 6 months to determine if the LDL-C reduction achieved with KYNAMRO is sufficiently robust to warrant the potential risk of liver toxicity.

2.2 Administration

Each pre-filled syringe of KYNAMRO provides 200 mg of mipomersen sodium in a deliverable volume of 1 milliliter (mL) of solution and is intended for single-use only.

The KYNAMRO pre-filled syringe should be removed from 2-8°C (36-46°F) refrigerated storage and allowed to reach room temperature for at least 30 minutes prior to administration.

Parenteral drug products should be inspected visually prior to administration. If the solution is cloudy or contains visible particulate matter, the contents must not be injected and the product should be returned to the pharmacy.

The first injection administered by the patient or caregiver should be performed under the guidance and supervision of an appropriately qualified health care professional.

KYNAMRO should be injected into the abdomen, thigh region, or outer area of the upper arm. KYNAMRO should not be injected in areas of active skin disease or injury such as sunburns, skin rashes, inflammation, skin infections, active areas of psoriasis, etc. Areas of tattooed skin and scarring should also be avoided.

2.3 Adjustments for Patients Developing Transaminase Elevations

Table 1 summarizes recommendations for monitoring for patients who develop elevated transaminases during therapy with KYNAMRO [see Warnings and Precautions (5.1)].
Table 1: Monitoring for Patients With Elevated Transaminases * Recommendations based on an ULN of approximately 30-40 international units/L. ALT or AST Treatment and monitoring recommendations* ≥ 3x and < 5x ULN Confirm elevation with a repeat measurement within one week. If confirmed, withhold dosing, obtain additional liver-related tests if not already measured (such as total bilirubin, alkaline phosphatase and INR) and investigate to identify the probable cause. If resuming KYNAMRO after transaminases resolve to <3x ULN consider monitoring liver-related tests more frequently. ≥ 5x ULN Withhold dosing, obtain additional liver-related tests if not already measured (such as total bilirubin, alkaline phosphatase and INR) and investigate to identify the probable cause. If resuming KYNAMRO after transaminases resolve to <3x ULN, monitor liver-related tests more frequently.
If transaminase elevations are accompanied by clinical symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥ 2x ULN, or active liver disease, discontinue treatment with KYNAMRO and investigate to identify the probable cause [see Warnings and Precautions (5.1)].
Aldurazyme

Aldurazyme

2.1 Recommended Dose

The recommended dosage regimen of ALDURAZYME is 0.58 mg/kg of body weight administered once weekly as an intravenous (IV) infusion. Pretreatment is recommended 60 minutes prior to the start of the infusion and may include antihistamines, antipyretics, or both [see Warnings and Precautions (5)].

Each vial of ALDURAZYME provides 2.9 milligrams (mg) of laronidase in 5.0 milliliters (mL) of solution and is intended for single use only. Do not use the vial more than one time. The concentrated solution for infusion must be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 mL or 250 mL, using aseptic techniques. The final volume of the infusion is determined by the patient’s body weight. Patients with a body weight of 20 kg or less should receive a total volume of 100 mL. Patients with a body weight greater than 20 kg should receive a total volume of 250 mL [see Dosage and Administration (2.2)]. For patients with underlying cardiac or respiratory compromise and weighing up to 30 kg, physicians may consider diluting ALDURAZYME in a volume of 100 mL and administering at a decreased infusion rate [see Dosage and Administration (2.2), Warnings and Precautions (5.3) and Adverse Reactions (6.3)].

2.2 Instructions for Use

Prepare and use ALDURAZYME according to the following steps. Use aseptic techniques. Prepare ALDURAZYME using low-protein-binding containers and administer with a low-protein-binding infusion set equipped with an in-line, low-protein-binding 0.2 micrometer (µm) filter. There is no information on the compatibility of diluted ALDURAZYME with glass containers.
Determine the number of vials to be diluted based on the patient's weight and the recommended dose of 0.58 mg/kg, using the following equation: Patient's weight (kg) x 1 mL/kg of ALDURAZYME = Total number mL of ALDURAZYME Total number mL of ALDURAZYME ÷ 5 mL per Vial = Total number of Vials. Round up to the next whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not heat or microwave vials. Before withdrawing the ALDURAZYME from the vial, visually inspect each vial for particulate matter and discoloration. The ALDURAZYME solution should be clear to slightly opalescent and colorless to pale yellow. Some translucency may be present in the solution. Do not use if the solution is discolored or if there is particulate matter in the solution. Withdraw and discard a volume of the 0.9% Sodium Chloride Injection, USP from the infusion bag, equal to the volume of ALDURAZYME concentrate to be added. Slowly withdraw the calculated volume of ALDURAZYME from the appropriate number of vials using caution to avoid excessive agitation. Do not use a filter needle, as this may cause agitation. Agitation may denature ALDURAZYME, rendering it biologically inactive. Slowly add the ALDURAZYME solution to the 0.9% Sodium Chloride Injection, USP using care to avoid agitation of the solutions. Do not use a filter needle. Gently rotate the infusion bag to ensure proper distribution of ALDURAZYME. Do not shake the solution. The entire infusion volume (100 mL for patients weighing 20 kg or less and 250 mL for patients weighing greater than 20 kg) should be delivered over approximately 3 to 4 hours. The initial infusion rate of 10 µg/kg/hr may be incrementally increased every 15 minutes during the first hour, as tolerated, until a maximum infusion rate of 200 µg/kg/hr is reached. The maximum rate is then maintained for the remainder of the infusion (2-3 hours), as outlined in Tables 1 and 2. Administer the diluted ALDURAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter. Table 1: Incremental Rates for 100 mL ALDURAZYME® Infusion (For use with Patients Weighing 20 kg or Less) Infusion Rate Criteria for Increasing Infusion Rate 2 mL/hr x 15 minutes (10 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 4 mL/hr x 15 minutes (20 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 8 mL/hr x 15 minutes (50 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 16 mL/hr x 15 minutes (100 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 32 mL/hr x ~3 hours (200 μg/kg/hr) For the remainder of the infusion. Table 2: Incremental Rates for 250 mL ALDURAZYME® Infusion (For use with Patients Weighing Greater than 20 kg) Infusion Rate Criteria for Increasing Infusion Rate 5 mL/hr x 15 minutes (10 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 10 mL/hr x 15 minutes (20 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 20 mL/hr x 15 minutes (50 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 40 mL/hr x 15 minutes (100 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 80 mL/hr x ~3 hours (200 μg/kg/hr) For the remainder of the infusion.
ALDURAZYME does not contain any preservatives; therefore, after dilution with saline, the infusion bags should be used immediately. If immediate use is not possible, the diluted solution should be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 36 hours. Other than during infusion, room temperature storage of diluted solution is not recommended. Any unused product or waste material should be discarded and disposed of in accordance with local requirements.

ALDURAZYME must not be administered with other medicinal products in the same infusion. The compatibility of ALDURAZYME in solution with other products has not been evaluated.
Lumizyme

Lumizyme

2.1 Recommended Dose

The recommended dosage of alglucosidase alfa is 20 mg/kg body weight administered every 2 weeks as an intravenous infusion.

2.2 Instructions for Use

Alglucosidase alfa does not contain any preservatives. Vials are single-use only. Discard any unused product.

The total volume of infusion is determined by the patient's body weight and should be administered over approximately 4 hours. Infusions should be administered in a step-wise manner using an infusion pump. The initial infusion rate should be no more than 1 mg/kg/hr. The infusion rate may be increased by 2 mg/kg/hr every 30 minutes, after patient tolerance to the infusion rate is established, until a maximum rate of 7 mg/kg/hr is reached. Vital signs should be obtained at the end of each step. If the patient is stable, alglucosidase alfa may be administered at the maximum rate of 7 mg/kg/hr until the infusion is completed. The infusion rate may be slowed or temporarily stopped in the event of mild to moderate hypersensitivity reactions. In the event of anaphylaxis or severe hypersensitivity reaction, immediately discontinue administration of alglucosidase alfa, and initiate appropriate medical treatment. See Table 1 below for the rate of infusion at each step, expressed as mL/hr based on the recommended infusion volume by patient weight.
Table 1: Recommended Infusion Volumes and Rates Patient Weight Range (kg) Total infusion volume (mL) Step 11 mg/kg/hr(mL/hr) Step 23 mg/kg/hr(mL/hr) Step 35 mg/kg/hr(mL/hr) Step 47 mg/kg/hr(mL/hr) 1.25 -10 50 3 8 13 18 10.1 - 20 100 5 15 25 35 20.1 – 30 150 8 23 38 53 30.1 – 35 200 10 30 50 70 35.1 – 50 250 13 38 63 88 50.1 – 60 300 15 45 75 105 60.1 – 100 500 25 75 125 175 100.1 – 120 600 30 90 150 210 120.1 – 140 700 35 105 175 245 140.1 – 160 800 40 120 200 280 160.1 – 180 900 45 135 225 315 180.1 – 200 1,000 50 150 250 350
2.3 Reconstitution, Dilution, and Administration

Alglucosidase alfa should be reconstituted, diluted and administered by a healthcare professional.

Use aseptic technique during preparation. Do not use filter needles during preparation.
a. Determine the number of vials to be reconstituted based on the individual patient's weight and the recommended dose of 20 mg/kg.
Patient weight (kg) × dose (mg/kg) = patient dose (in mg)

Patient dose (in mg) divided by 50 mg/vial = number of vials to reconstitute. If the number of vials includes a fraction, round up to the next whole number.

Example: Patient weight (68 kg) × dose (20 mg/kg) = patient dose (1,360 mg)

1,360 mg divided by 50 mg/vial = 27.2 vials; therefore, 28 vials should be reconstituted.

Remove the required number of vials from the refrigerator and allow them to reach room temperature prior to reconstitution (approximately 30 minutes).
b. Reconstitute each alglucosidase alfa vial by slowly injecting 10.3 mL of Sterile Water for Injection, USP to the inside wall of each vial. Each vial will yield a concentration of 5 mg/mL. The total extractable dose per vial is 50 mg per 10 mL. Avoid forceful impact of the water for injection on the powder and avoid foaming. This is done by slow drop-wise addition of the water for injection down the inside of the vial and not directly onto the lyophilized cake. Tilt and roll each vial gently. Do not invert, swirl, or shake. c. The reconstituted alglucosidase alfa solution should be protected from light. d. Perform an immediate visual inspection on the reconstituted vials for particulate matter and discoloration. If upon immediate inspection opaque particles are observed or if the solution is discolored do not use. The reconstituted solution may occasionally contain some alglucosidase alfa particles (typically less than 10 in a vial) in the form of thin white strands or translucent fibers subsequent to the initial inspection. This may also happen following dilution for infusion. These particles have been shown to contain alglucosidase alfa and may appear after the initial reconstitution step and increase over time. Studies have shown that these particles are removed via in-line filtration without having a detectable effect on the purity or strength. e. Alglucosidase alfa should be diluted in 0.9% Sodium Chloride for Injection, USP, immediately after reconstitution, to a final alglucosidase alfa concentration of 0.5 to 4 mg/mL. See Table 1 for the recommended total infusion volume based on patient weight. f. Slowly withdraw the reconstituted solution from each vial. Avoid foaming in the syringe. g. Remove airspace from the infusion bag to minimize particle formation due to the sensitivity of alglucosidase alfa to air-liquid interfaces. h. Add the reconstituted alglucosidase alfa solution slowly and directly into the sodium chloride solution. Do not add directly into airspace that may remain within the infusion bag. Avoid foaming in the infusion bag. i. Gently invert or massage the infusion bag to mix. Do not shake. j. Administer alglucosidase alfa using an in-line low protein binding 0.2 µm filter. k. Do not infuse alglucosidase alfa in the same intravenous line with other products.
The reconstituted and diluted solution should be administered without delay. If immediate use is not possible, the reconstituted and diluted solution is stable for up to 24 hours at 2°C to 8°C (36°F to 46°F). Storage of the reconstituted solution at room temperature is not recommended. The reconstituted and diluted alglucosidase alfa solution should be protected from light. Do not freeze or shake.

Alglucosidase alfa does not contain any preservatives. Vials are single-use only. Discard any unused product.
Renvela

Renvela

Because of the rapid reaction with the hydrochloric acid in the stomach, the dosing of Renvela powder or tablet is anticipated to be similar to that of the sevelamer hydrochloride salt or tablet.

2.1 General Dosing Information

Renvela should be given three times a day with meals.

Patients Not Taking a Phosphate Binder. The recommended starting dose of Renvela is 0.8 to 1.6 g with meals based on serum phosphorus level. Table 1 provides recommended starting doses of Renvela for patients not taking a phosphate binder.
Table 1. Starting Dose for Dialysis Patients Not Taking a Phosphate Binder Serum Phosphorus Renvela® 800 mg Tablet Renvela Powder > 5.5 and < 7.5 mg/dL 1 tablet three times daily with meals 0.8 g three times daily with meals ≥ 7.5 mg/dL 2 tablets three times daily with meals 1.6 g three times daily with meals
Switching from Sevelamer Hydrochloride Tablets. For patients switching from sevelamer hydrochloride tablets to sevelamer carbonate tablets or powder, use the same dose in grams. Further titration may be necessary to achieve desired phosphorus levels. The highest daily dose of sevelamer carbonate studied was 14 grams in CKD patients on dialysis.

Switching between Sevelamer Carbonate Tablets and Powder. Use the same dose in grams. Further titration may be necessary to achieve desired phosphorus levels.

Switching from Calcium Acetate. In a study in 84 CKD patients on hemodialysis, a similar reduction in serum phosphorus was seen with equivalent doses (approximately mg for mg) of sevelamer hydrochloride and calcium acetate. Table 2 gives recommended starting doses of Renvela based on a patient's current calcium acetate dose.
Table 2. Starting Dose for Dialysis Patients Switching From Calcium Acetate to Renvela Calcium Acetate 667 mg(Tablets per meal) Renvela® 800 mg Tablet(Tablets per meal) Renvela Powder 1 tablet 1 tablet 0.8 g 2 tablets 2 tablets 1.6 g 3 tablets 3 tablets 2.4 g
Dose Titration for All Patients Taking Renvela. Titrate the Renvela dose by 0.8 g three times per day with meals at two-week intervals as necessary with the goal of controlling serum phosphorus within the target range.

2.2 Sevelamer Carbonate Powder Preparation Instructions

The entire contents of each 0.8 or 2.4 g packet should be placed in a cup and mixed thoroughly with the amount of water described in Table 3.
Table 3. Sevelamer Carbonate Powder Preparation Instructions Renvela PowderPacket Strength Minimum amount of water for dose preparation (either ounces, mL or teaspoon/Tablespoon) ounces mL tsp/Tbsp 0.8 g 1 30 6 teaspoons/2 Tablespoons 2.4 g 2 60 4 Tablespoons
Multiple packets may be mixed together with the appropriate amount of water. Patients should be instructed to stir the mixture vigorously (it does not dissolve) and drink the entire preparation within 30 minutes and resuspend the preparation right before drinking.

Based on clinical studies, the average prescribed daily dose of sevelamer carbonate is approximately 7.2 g per day.
Cerdelga

Cerdelga

2.1 Patient Selection

Select patients with Gaucher disease type 1 based on their CYP2D6 metabolizer status. It is recommended patient genotypes be established using an FDA-cleared test for determining CYP2D6 genotype [see Indications and Usage (1)].

2.2 Recommended Adult Dosage

The recommended dosage of CERDELGA is 84 mg twice daily in CYP2D6 EMs and IMs. The recommended dosage in CYP2D6 PMs is 84 mg once daily; appropriate adverse event monitoring is recommended [see Adverse Reactions (6.1)]. The predicted exposures with 84 mg once daily in patients who are CYP2D6 PMs are expected to be similar to exposures observed with 84 mg twice daily in CYP2D6 IMs [see Clinical Pharmacology (12.3)].

Some inhibitors of CYP2D6 and CYP3A are contraindicated with CERDELGA depending on the patient's metabolizer status [see Contraindications (4)]. Co-administration of CERDELGA with other CYP2D6 and CYP3A inhibitors may require dosage adjustment depending on the patient's CYP2D6 metabolizer status to reduce the risk of potentially significant adverse reactions [see Table 3 and Table 4 in Drug Interactions (7.1)].

Reduce the dosage of CERDELGA to 84 mg once daily for:
CYP2D6 EMs and IMs taking strong or moderate CYP2D6 inhibitors CYP2D6 EMs taking strong or moderate CYP3A inhibitors
2.3 Important Administration Instructions
Swallow capsules whole, preferably with water, and do not crush, dissolve, or open the capsules. CERDELGA can be taken with or without food. Avoid the consumption of grapefruit or grapefruit juice with CERDELGA because grapefruit is a strong CYP3A inhibitor [see Drug Interactions (7.1)]. If a dose of CERDELGA is missed, take the prescribed dose at the next scheduled time; do not double the next dose. For patients currently treated with imiglucerase, velaglucerase alfa, or taliglucerase alfa, CERDELGA may be administered 24 hours after the last dose of the previous enzyme replacement therapy (ERT).
Campath

Campath

2.1 Dosing Schedule and Administration
Administer as an IV infusion over 2 hours. Do not administer as intravenous push or bolus. Recommended Dosing Regimen Gradually escalate to the maximum recommended single dose of 30 mg. Escalation is required at initiation of dosing or if dosing is held ≥ 7 days during treatment. Escalation to 30 mg ordinarily can be accomplished in 3 - 7 days. Escalation Strategy: Administer 3 mg daily until infusion reactions are ≤ grade 2 [see ADVERSE REACTIONS (6.1)]. Then administer 10 mg daily until infusion reactions are ≤ grade 2. Then administer 30 mg/day three times per week on alternate days (e.g., Mon-Wed-Fri). The total duration of therapy, including dose escalation, is 12 weeks. Single doses of greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia.
2.2 Recommended Concomitant Medications
Premedicate with diphenhydramine (50 mg) and acetaminophen (500-1000 mg) 30 minutes prior to first infusion and each dose escalation. Institute appropriate medical management (e.g. steroids, epinephrine, meperidine) for infusion reactions as needed [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.2) and ADVERSE REACTIONS (6.1)]. Administer trimethoprim/sulfamethoxazole DS twice daily (BID) three times per week (or equivalent) as Pneumocystis jiroveci pneumonia (PCP) prophylaxis. Administer famciclovir 250 mg BID or equivalent as herpetic prophylaxis.
Continue PCP and herpes viral prophylaxis for a minimum of 2 months after completion of Campath or until the CD4+ count is ≥ 200 cells/µL, whichever occurs later [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.3)].

2.3 Dose Modification
Withhold Campath during serious infection or other serious adverse reactions until resolution. Discontinue Campath for autoimmune anemia or autoimmune thrombocytopenia. There are no dose modifications recommended for lymphopenia.

Dose Modification for Neutropenia or Thrombocytopenia [see WARNINGS AND PRECAUTIONS (5.1)] * If the delay between dosing is ≥ 7 days, initiate therapy at Campath 3 mg and escalate to 10 mg and then to 30 mg as tolerated [see DOSAGE AND ADMINISTRATION (2.1)].
Hematologic Values

Dose Modification*

ANC < 250/μL and/or platelet count ≤25,000/μL

For first occurrence:

Withhold Campath therapy. Resume Campathat 30 mg when ANC ≥ 500/μL and platelet count ≥ 50,000/μL.

For second occurrence:

Withhold Campath therapy. Resume Campathat 10 mg when ANC ≥ 500/μL and platelet count ≥ 50,000/μL.

For third occurrence:

Discontinue Campath therapy.

≥ 50% decrease from baseline in patients initiating therapy with a baseline ANC ≤ 250/μL and/or a baseline platelet count ≤ 25,000/μL

For first occurrence:

Withhold Campath therapy. Resume Campathat 30 mg upon return to baseline value(s).

For second occurrence:

Withhold Campath therapy. Resume Campathat 10 mg upon return to baseline value(s).

For third occurrence:

Discontinue Campath therapy.

2.4 Preparation and Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present or the solution is discolored, the vial should not be used. DO NOT SHAKE VIAL.

Use aseptic technique during the preparation and administration of Campath. Withdraw the necessary amount of Campath from the vial into a syringe.
To prepare the 3 mg dose, withdraw 0.1 mL into a 1 mL syringe calibrated in increments of 0.01 mL. To prepare the 10 mg dose, withdraw 0.33 mL into a 1 mL syringe calibrated in increments of 0.01 mL. To prepare the 30 mg dose, withdraw 1 mL in either a 1 mL or 3 mL syringe calibrated in 0.1 mL increments.
Inject syringe contents into 100 mL sterile 0.9% Sodium Chloride USP or 5% Dextrose in Water USP. Gently invert the bag to mix the solution. Discard syringe.

The vial contains no preservatives and is intended for single use only. DISCARD VIAL including any unused portion after withdrawal of dose.

Use within 8 hours after dilution. Store diluted Campath at room temperature (15-30°C) or refrigerated (2-8°C). Protect from light.

2.5 Incompatibilities

Campath is compatible with polyvinylchloride (PVC) bags and PVC or polyethylene-lined PVC administration sets. Do not add or simultaneously infuse other drug substances through the same intravenous line.

2.1 Dosing Schedule and Administration
Administer as an IV infusion over 2 hours. Do not administer as intravenous push or bolus. Recommended Dosing Regimen Gradually escalate to the maximum recommended single dose of 30 mg. Escalation is required at initiation of dosing or if dosing is held ≥ 7 days during treatment. Escalation to 30 mg ordinarily can be accomplished in 3 - 7 days. Escalation Strategy: Administer 3 mg daily until infusion reactions are ≤ grade 2 [see ADVERSE REACTIONS (6.1)]. Then administer 10 mg daily until infusion reactions are ≤ grade 2. Then administer 30 mg/day three times per week on alternate days (e.g., Mon-Wed-Fri). The total duration of therapy, including dose escalation, is 12 weeks. Single doses of greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia.
2.2 Recommended Concomitant Medications
Premedicate with diphenhydramine (50 mg) and acetaminophen (500-1000 mg) 30 minutes prior to first infusion and each dose escalation. Institute appropriate medical management (e.g. steroids, epinephrine, meperidine) for infusion reactions as needed [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.2) and ADVERSE REACTIONS (6.1)]. Administer trimethoprim/sulfamethoxazole DS twice daily (BID) three times per week (or equivalent) as Pneumocystis jiroveci pneumonia (PCP) prophylaxis. Administer famciclovir 250 mg BID or equivalent as herpetic prophylaxis.
Continue PCP and herpes viral prophylaxis for a minimum of 2 months after completion of Campath or until the CD4+ count is ≥ 200 cells/µL, whichever occurs later [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.3)].

2.3 Dose Modification
Withhold Campath during serious infection or other serious adverse reactions until resolution. Discontinue Campath for autoimmune anemia or autoimmune thrombocytopenia. There are no dose modifications recommended for lymphopenia.

Dose Modification for Neutropenia or Thrombocytopenia [see WARNINGS AND PRECAUTIONS (5.1)] * If the delay between dosing is ≥ 7 days, initiate therapy at Campath 3 mg and escalate to 10 mg and then to 30 mg as tolerated [see DOSAGE AND ADMINISTRATION (2.1)].
Hematologic Values

Dose Modification*

ANC < 250/μL and/or platelet count ≤25,000/μL

For first occurrence:

Withhold Campath therapy. Resume Campathat 30 mg when ANC ≥ 500/μL and platelet count ≥ 50,000/μL.

For second occurrence:

Withhold Campath therapy. Resume Campathat 10 mg when ANC ≥ 500/μL and platelet count ≥ 50,000/μL.

For third occurrence:

Discontinue Campath therapy.

≥ 50% decrease from baseline in patients initiating therapy with a baseline ANC ≤ 250/μL and/or a baseline platelet count ≤ 25,000/μL

For first occurrence:

Withhold Campath therapy. Resume Campathat 30 mg upon return to baseline value(s).

For second occurrence:

Withhold Campath therapy. Resume Campathat 10 mg upon return to baseline value(s).

For third occurrence:

Discontinue Campath therapy.

2.4 Preparation and Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present or the solution is discolored, the vial should not be used. DO NOT SHAKE VIAL.

Use aseptic technique during the preparation and administration of Campath. Withdraw the necessary amount of Campath from the vial into a syringe.
To prepare the 3 mg dose, withdraw 0.1 mL into a 1 mL syringe calibrated in increments of 0.01 mL. To prepare the 10 mg dose, withdraw 0.33 mL into a 1 mL syringe calibrated in increments of 0.01 mL. To prepare the 30 mg dose, withdraw 1 mL in either a 1 mL or 3 mL syringe calibrated in 0.1 mL increments.
Inject syringe contents into 100 mL sterile 0.9% Sodium Chloride USP or 5% Dextrose in Water USP. Gently invert the bag to mix the solution. Discard syringe.

The vial contains no preservatives and is intended for single use only. DISCARD VIAL including any unused portion after withdrawal of dose.

Use within 8 hours after dilution. Store diluted Campath at room temperature (15-30°C) or refrigerated (2-8°C). Protect from light.

2.5 Incompatibilities

Campath is compatible with polyvinylchloride (PVC) bags and PVC or polyethylene-lined PVC administration sets. Do not add or simultaneously infuse other drug substances through the same intravenous line.

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